The aims of this research are three-fold (1) a clinical trial of 1-serine in schizophrenia, (2) a clinical study of the regulation of the activity of the enzymes of the one-carbon cycle dehydrogenase in normal individuals and in schizophrenic patients, (3) an in vitro study of the regulatory biochemistry of the one-carbon cycle in the synaptic region of the mammalian brain. It has been established: 40 percent of chronic schizophrenics respond to 20 g/day of 1-methionine (approximately 250 milligrams/kg) with an acute florid psychotic reaction whereas normal individuals as far as is known do not; and 1-methionine (250 milligrams/kg) will disrupt conditioned behavior in rats, and this effect is abolished by 1- serine. This disruption of behavior by 1-methionine in schizophrenics and in rats may depend on a complex series of biochemical reactions in the brain, because the amino acid is involved in, among other things, the one-carbon cycle and transmethylation reactions. Of the various enzymes involved in one-carbon cycle reactions, most is known about serine transhydroxymethylase, and a defect in its regulation could lead to serious perturbation of this critical cycle. We therefore propose to study this in schizophrenics. We also propose to conduct further work on certain other enzymes of the one-carbon cycle in mammalian brain, by subcellularly localizing the individual enzymes and by characterizing the separate synaptosomal enzymes. These studies may in turn enable us to study the function of these other enzymes in schizophrenics.